Cortical Alterations in H3K27ac Regulation in Gene Expression Coincide Associated with Cognitive Decline and Affective Behavior in Mice During Aging: Genome-wide Epigenetic Analysis

Histone acetylation plays a critical role in the regulation of gene expression in humans and animals, influencing various biological processes, including brain function during aging. Understanding the alterations in histone acetylation during aging could provide insights into the molecular mechanisms underlying age-related cognitive decline. In this study, we investigated the dynamics of histone acetylation and its functional effects in the brain during aging by characterizing and comparing differences in memory and affective behavior, histone H3 levels, expression of histone-modifying enzymes HDACs and HAT, genome-wide H3K27ac abundancy, an active enhancer, and gene expression between young (2-3 months old) and aged (18-20 months old) genetically identical mice. Our results demonstrate that aging induces a variety behavioral phenotypes including a decline in activity/locomotion, increase in anxiety, and memory impairment, that occurs in conjunction with dysregulation of HDAC 1, 2, and 3, HAT p300 and genome-wide differential abundancy of H3K27ac at a variety of gene promoters. Importantly, we also demonstrated that age-related reductions in H3K27ac at gene promoters were associated with decreased expression levels of genes related to DNA damage and aging including Map3K1, Rev1, and Cdk2ap1. Overall, our study suggests the role of histone acetylation as a regulator of gene expression during brain aging and that changes in histone acetylation are associated with age-related alterations in memory and cognitive decline.